Wang Huanhuan, Hu Xiaoyun, Wang Teng, Cui Cheng, Jiang Ji, Dong Kai, Chen Shuai, Jin Chunyan, Zhao Qian, Du Bin, Hu Pei
Clinical Pharmacology Research Center and State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Beijing, China.
Front Pharmacol. 2021 Apr 19;12:645130. doi: 10.3389/fphar.2021.645130. eCollection 2021.
Kukoamine B, a small molecule compound, is being developed for the treatment of sepsis in a Phase II clinical trial. The objective of this study was to optimize dosing selection for a Phase IIb clinical trial using an exposure-response model. Data of 34 sepsis patients from a Phase IIa clinical trial were used in the model: 10 sepsis patients from the placebo group and a total of 24 sepsis patients from the 0.06 mg/kg, 0.12 mg/kg, and 0.24 mg/kg drug groups. Exposure-response relationship was constructed to model the impact of the standard care therapy and area under curve (AUC) of kukoamine B to the disease biomarker (SOFA score). The model was evaluated by goodness of fit and visual predictive check. The simulation was performed 1,000 times based on the built model. The data of the placebo and the drug groups were pooled and modeled by a nonlinear mixed-effect modeling approach in sepsis. A latent-variable approach in conjunction with an inhibitory indirect response model was used to link the standard care therapy effect and drug exposure to SOFA score. The maximum fraction of the standard care therapy was estimated to 0.792. The eliminate rate constant of the SOFA score was 0.263/day for the standard care therapy. The production rate of SOFA score (K) was estimated at 0.0569/day and the AUC at half the maximal drug effect (EAUC) was estimated at 1,320 hng/mL. Model evaluation showed that the built model could well describe the observed SOFA score. Model-based simulations showed that the SOFA score on day 7 decreased to a plateau when AUC increased to 1,500 hng/mL. We built an exposure-response model characterizing the pharmacological effect of kukoamine B from the standard care therapy in sepsis patients. A dose regimen of 0.24 mg/kg was finally recommended for the Phase IIb clinical trial of kukoamine B based on modeling and simulation results.
苦柯胺B是一种小分子化合物，正在进行II期临床试验以治疗脓毒症。本研究的目的是使用暴露-反应模型优化IIb期临床试验的给药方案选择。模型中使用了来自IIa期临床试验的34例脓毒症患者的数据：安慰剂组的10例脓毒症患者以及0.06 mg/kg、0.12 mg/kg和0.24 mg/kg药物组的共24例脓毒症患者。构建暴露-反应关系以模拟标准治疗和苦柯胺B的曲线下面积（AUC）对疾病生物标志物（序贯器官衰竭评估（SOFA）评分）的影响。通过拟合优度和可视化预测检查对模型进行评估。基于构建的模型进行了1000次模拟。安慰剂组和药物组的数据进行合并，并采用非线性混合效应建模方法对脓毒症进行建模。使用潜变量方法结合抑制性间接反应模型将标准治疗效果和药物暴露与SOFA评分联系起来。标准治疗的最大分数估计为0.792。标准治疗的SOFA评分消除速率常数为0.263/天。SOFA评分的产生速率（K）估计为0.0569/天，最大药物效应一半时的AUC（EAUC）估计为1320 hng/mL。模型评估表明，构建的模型能够很好地描述观察到的SOFA评分。基于模型的模拟表明，当AUC增加到1500 hng/mL时，第7天的SOFA评分降至平台期。我们构建了一个暴露-反应模型，以表征脓毒症患者中标准治疗的苦柯胺B的药理作用。基于建模和模拟结果，最终推荐0.24 mg/kg的给药方案用于苦柯胺B的IIb期临床试验。
